Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Profound metabolic changes occur during ischemia, often leading to cell and organ death. The elicitation of new blood vessels, in an effort to mitigate ischemic damage, is part of a critical cellular and tissue response to ischemia. How metabolic activity and vascular homeostasis are coordinated, however, remains poorly understood. We have uncovered a novel pathway that regulates neovascularization in response to ischemia. Integral to this pathway are two transcriptional coactivators, PGC-1a (ppargc1a) and its close relative PGC-1[unreadable] (ppargc1b). These proteins are well-known, powerful regulators of mitochondria and other metabolic processes. These coactivators thus directly link oxidative metabolism to angiogenesis, and they potentially coordinate the delivery of oxygen and substrates with their consumption. The identification of this novel angiogenic pathway raises a number of critical questions. The mechanism by which PGC-1a responds to ischemia remains unknown. The molecular mechanisms by which the PGC-1 coactivators regulate angiogenesis also remain incompletely defined. And finally, whether and how the PGC-1 coactivators can protect against limb ischemia in the adult needs further investigation. We propose here to examine these questions in close detail, both in cell culture and in intact animals. A number of genetic mouse models will be used, as well as well-established mouse models of limb ischemia and angiogenesis. The major goal of this proposal is to understand the molecular means by which PGC-1a and [unreadable] regulate angiogenesis. Investigating whether and how alterations in PGC-1a and/or [unreadable] can modulate angiogenesis may set the stage for the development of new classes of therapeutic drugs to treat ischemic diseases. PUBLIC HEALTH RELEVANCE: Occlusion of blood vessels in the heart, brain, or limbs is a leading cause of death worldwide. The creation of new blood vessels in response to such events can be critical to tissue function and survival. We have uncovered a novel pathway that regulates the formation of new blood vessels. We propose here to examine this new pathway in close detail. These investigations may set the stage for the development of new classes of therapeutic drugs for ischemic diseases, as well as other diseases in which the formation of new blood vessels can be critical.